Project Summary: Tumor progression toward a malignant, metastatic disease state involves complex interactions between tumor cells and the host microenvironment. One such crucial interaction involves recruitment of tumor blood vessels through angiogenesis, which provides the tumor with oxygen, nutrients, and an entry point into circulation through which metastatic cells may travel to and colonize distant organs. EphA2 receptor tyrosine kinase, which is expressed tumor endothelium, is a key regulator of tumor angiogenesis in vivo. Inhibition of EphA2 signaling through treatment with soluble receptors or host EphA2- deficiency severely impairs tumor neovascularization and lung metastasis in tumor-bearing animals. The goal of this proposal is to dissect the molecular mechanism(s) that couple ephrin-A1 ligand induced activation of endothelial EphA2 receptor to tumor angiogenesis by investigating the hypothesis that membrane anchored ephrin-A1 ligands expressed by tumor cells activate endothelial expressed EphA2 RTK, linking specific domains of the receptor to initiation of endothelial cell migration and neovascularization through a Vav/Rac-1 dependent mechanism. This research will enhance our understanding of the tumor microenvironment and the role it plays in malignant progression, an NCI priority for FY2006. Investigation will be completed at Vanderbilt University School of Medicine in the context of the Vanderbilt-lngram Comprehensive Cancer Center, with facilities and a host-tumor interaction focused research environment ideally suited for the molecular, biochemical, and genetic analyses involved in this research. As a first-generation college graduate, the mentored training I will receive during completion of the proposed research will provide me with the skills, model systems, and career development opportunities necessary to establish an independent academic research program and to secure funding as an independent investigator. Relevance: The goal of this research is to identify structural components of EphA2 that enable this receptor to respond to tumor signals and cause new blood vessels to colonize and support the tumor, permitting invasion and metastatic spread that ultimately lead to cancer death. Identifying these components will provide the foundation for molecularly-targeted drugs designed to block receptor function and therefore blood vessel recruitment, which could more effectively treat malignant cancer.